Download Gene Section EP400 (E1A binding protein p400) Atlas of Genetics and Cytogenetics

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in Oncology and Haematology
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Gene Section
Mini Review
EP400 (E1A binding protein p400)
Sandrine Tyteca
Chromatin and Cell Proliferation group, LBCMCP-UMR 5088 CNRS, Universite Paul Sabatier, Bat 4R3B1,
118 route de Narbonne, 31062 Toulouse Cedex 9, France
Published in Atlas Database: June 2007
Online updated version: http://AtlasGeneticsOncology.org/Genes/EP400ID40457ch12q24.html
DOI: 10.4267/2042/38461
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Isoform 1 retains an alternatively spliced sequence
inside intron 2.
Isoform 3 lacks exon 4.
Isoform 4 lacks exon 23.
Identity
Hugo: EP400
Other names: CAGH32; E1A binding protein p400;
hDomino; p400; TNRC12
Location: 12q24.33
Pseudogene
There is an EP400 pseudogene termed 'EP400 Nterminal like' (EP400-NL) in the same locus.
DNA/RNA
Description
Protein
The EP400 gene consists of 52 exons and spans 130.5
kb of genomic sequence on chromosome 12.
Description
The EP400 protein (isoform 2) is 3124 amino acids
long and its molecular weight is about 400 kDa. It was
cloned and characterized in 2001 thanks to its interation
with the E1A oncoprotein.
Isoform 1 produces a 3160 aa long protein.
Isoform 3 produces a 3087 aa long protein.
Isoform 4 produces a 3043 aa long protein.
Transcription
The predominant mRNA transcribed from this gene is
12,265 nt long. This is actually the isoform 2 of EP400.
Three other isoforms generated by alternative splicing
have been described:
Atlas Genet Cytogenet Oncol Haematol. 2008;12(1)
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EP400 (E1A binding protein p400)
Tyteca S
There has been no experimental confirmation for
isoforms 3 and 4.
The only described post-translational modification is a
phosphorylation on Ser736.
M. musculus: Ep400
R. norvegicus: Ep400
G. gallus: EP400
D. melanogaster: DOM or domino
Expression
Implicated in
No data.
Localisation
Cancers
EP400 belongs to chromatin remodelling complexes
which are located in the nucleus, so it is probably
nuclear. However, its cellular localization has not been
formally monitored to date.
Oncogenesis
It was shown that EP400 is a target for the E1A viral
oncoprotein transforming activity.
Indeed, studies showed that the overexpression of
specific EP400 fragments corresponding to the E1A
binding region (the SWI2/SNF2 domain) enhance the
ability of E1A to transform rat embryo fibroblasts in
the presence of ras. Moreover, the same fragments are
able to partially restore the transforming activity of a
tranformation-defective E1A mutant.
Function
EP400 belongs to the SWI2/SNF2 family of ATPases
and is found in two highly related chromatin
remodelling complexes: the Tip60 and p400
complexes. In these complexes, EP400 is associated
with other enzymes such as the Tip60 histone
acetyltransferase and/or the RuvBL1 and RuvBL2
helicases. (Note: putative specific functions of each
splicing variant have not been investigated to date)
Functions at the cellular level:
EP400 has been implicated in cell cycle control,
apoptosis and development.
First, the depletion of EP400 in untransformed human
fibroblasts leads to senescence through induction of the
p53 - p21 pathway. Likewise, the EP400 knock-down
induces a p21-dependent cell cycle arrest in human cell
lines. According to these results, EP400 seems to
favour cell proliferation.
On the other hand, EP400 is required for E1A-mediated
apoptosis. Similarly, EP400 is required for apoptosis
upon DNA damage in human cell lines. Thus, EP400
also favours apoptosis, possibly through preventing cell
cycle arrest.
Finally, the murine homolog of EP400 appears to be
involved in embryonic hematopoiesis.
Functions at the molecular level:
EP400 has ATP-dependent chromatin remodelling
activity. Accordingly, EP400 was shown to be recruited
along with the Tip60 complex on promoters by the cmyc and E2F transcription factors. Moreover, the
EP400 homolog in drosophila is able to exchange
specific histone variants at double-strand breaks.
References
Fuchs M, Gerber J, Drapkin R, Sif S, Ikura T, Ogryzko V, Lane
WS, Nakatani Y, Livingston DM. The p400 complex is an
essential E1A transformation target. Cell 2001;106(3):297-307.
Frank SR, Parisi T, Taubert S, Fernandez P, Fuchs M, Chan
HM, Livingston DM, Amati B. MYC recruits the TIP60 histone
acetyltransferase complex to chromatin. EMBO Rep
2003;4(6):575-580.
Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villen J,
Li J, Cohn MA, Cantley LC, Gygi SP. Large-scale
characterization of HeLa cell nuclear phosphoproteins. Proc
Natl Acad Sci USA 2004;101(33):12130-12135.
Kusch T, Florens L, Macdonald WH, Swanson SK, Glaser RL,
Yates JR 3rd, Abmayr SM, Washburn MP, Workman JL.
Acetylation by Tip60 is required for selective histone variant
exchange at DNA lesions. Science 2004;306(5704):20842087.
Chan HM, Narita M, Lowe SW, Livingston DM. The p400 E1Aassociated protein is a novel component of the p53 ---> p21
senescence pathway. Genes Dev 2005;19(2):196-201.
Samuelson AV, Narita M, Chan HM, Jin J, de Stanchina E,
McCurrach ME, Narita M, Fuchs M, Livingston DM, Lowe SW.
p400 is required for E1A to promote apoptosis. J Biol Chem
2005;280(23):21915-21923.
Tyteca S, Vandromme M, Legube G, Chevillard-Briet M,
Trouche D. Tip60 and p400 are both required for UV-induced
apoptosis but play antagonistic roles in cell cycle progression.
EMBO J 2006;25(8):1680-1689.
Flinterman MB, Mymryk JS, Klanrit P, Yousef AF, Lowe SW,
Caldas C, Gaken J, Farzaneh F, Tavassoli M. p400 function is
required for the adenovirus E1A-mediated suppression of
EGFR and tumour cell killing. Oncogene 2007;[Epub ahead of
print].
Ueda T, Watanabe-Fukunaga R, Ogawa H, Fukuyama H,
Higashi Y, Nagata S, Fukunaga R. Critical role of the
p400/mDomino chromatin-remodeling ATPase in embryonic
hematopoiesis. Genes Cells 2007;12(5):581-592.
Homology
EP400 contains the SNF2 N-terminal domain shared by
all ATPases of the SWI2/SNF2 family (SNF2, STH1,
RAD16, RAD54, ISWI...). It also bears helicasespecific domains (see diagram):
an helicase C-terminal domain;
an HSA domain;
a DEXH box which contains the ATP-binding region.
Putative homologs in other species (non exhaustive):
Atlas Genet Cytogenet Oncol Haematol. 2008;12(1)
This article should be referenced as such:
Tyteca S. EP400 (E1A binding protein p400). Atlas Genet
Cytogenet Oncol Haematol.2008;12(1):3-4.
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